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Characterizing interactions of HIV-1 integrase with viral DNA and the cellular cofactor LEDGF

Year: 2010
Type: article
Abstract: A hallmark of retroviral replication is the permanent integration of the viral genome into the host cell genome.This integration is mediated by the viral enzyme integrase (IN) which is bound to the ends of the viral DNA in the context of a large nucleoprotein complex known as the pre-integration complex (PIC).Using the two catalytic activities of IN, the viral DNA ends are first processed then used for a strand transfer reaction that simultaneously breaks the host DNA backbone and ligates the viral genome into it.For HIV-1, the site of integration into the host genome is non-random and occurs most often in active transcription units.This bias is likely explained by the recruitment of pre-integration complexes to chromatin via interactions between IN and the cellular protein Lens Epithelium-Derived Growth Factor (LEDGF).Failure of either enzymatic reaction or failure of the PIC to engage chromatin is a replicative dead end for the virus.Integrase has long been considered an attractive therapeutic target due to its essential role in replication and its lack of a cellular counterpart.The first-inclass HIV IN inhibitors block integration by binding specifically to the IN-viral DNA complex, displacing the viral DNA ends from the active site and effectively preventing strand transfer.The specificity of this inhibition led to the rapid emergence of HIV-1 phenotypes resistant to all available strand transfer I would like to thank my advisor Mamuka Kvaratskhelia for his mentorship and the many opportunities I have had while working in his lab.Furthermore, my co-workers in the Kvaratskhelia lab have contributed enormously to the work presented herein.I would in particular like to thank Zhuojun Zhao, Jacques Kessl, Jocelyn Eidahl, and Nick Shkriabai for their technical assistance and friendship.I am indebted to our many
Language: English
Subfield: Virology
Open Access status: green
OpenAlex ID: W2240291902
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